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CRISPR-CAS9 REVOLUTION- A LOOK AT THE GENOME EDITING TOOL AND LACK OF LEGAL FRAMEWORK IN INDIA

Introduction

Modern biological science consists of an in-depth study and understanding of the living organism. This involves a thorough investigation of the gene, its biochemical structure, and mechanism. Rapid biotechnological advancements in recent years have led to change in the way genetic engineering, i.e., manipulating the organism’s gene or genome (i.e., the entire set of deoxyribonucleic acid of the organism) is done. The emergence of Clustered Regulatory Interspaced Short Palindromic Repeats (hereinafter “CRISPR” or “CRISPR-Cas9” or “Cas-9”) as a gene-editing tool is a representation of the development in science.

CRISPR-Cas9 is seen as the greatest biotechnological discovery by scientists and researchers[1]. The technology holds the ability to comprehend diseases using cells and act as defense systems for the bacteria and prevent single gene-based disorders quickly and efficiently. This gene-editing tool is seen as a piece of machinery that revolutionizes biology, medicine, and agriculture; and the way humans live[2]. In this piece, the author discusses the CRISPR-Cas9 technology as a gene-editing tool with a specific emphasis on its ethical and safety concerns. In light of these concerns, the author has analyzed the current legal and regulatory framework applicable to genetic editing. The article concludes with a recommendation of enacting legislation governing germ-line gene-editing in India.

The CRISPR-Cas9 System- How Does It Work?

The CRISPR-Cas9 system is a scientific tool that has led to the development of genetic modification practices. Under this system, scientists can easily perform a “genome-surgery,” which allows them to make alterations or changes to an organism’s genetic code[3]. It requires identifying specific enzymes that cut the DNA at site-specific nuclei to edit the target gene in a given cell. After the required alterations are done segment is replaced with a customized DNA. These specific alterations are done by adding, removing, or simply modifying the organism’s genetic material.

‘Dangerous’ Experiments and CRISPR-Cas9: Rise in Ethical and Safety Concerns

It is said that the CRISPR-Cas9 system is a significant biological advancement to the traditional gene-editing technology approach. Genome editing technology allows researchers and scientists to add, remove, and alter at specific genome sites. CRISP-Cas9 is a new and improved approach to genome editing technologies. Under the CRISPR-Cas9 system, there is precise cutting, addition, removal, and modification of genes using RNA-guided engineered nucleases. The CRISPR-Cas9 system preserves the genetic memory of a virus or infection and creates foreign DNA segments, namely CRISPR arrays. Whenever there is another attack, the CRISPR arrays produce bacteria that further produce RNA segments to target the virus's DNA and end up disabling it. After cutting the DNA, the cell's DNA repair machinery is used to make changes to the DNA and replaces the existing DNA with a customized one. The considerable excitement about CRISPR-Cas9 is attributed to its ability to manipulate the gene, including homologous recombination, and utilizing RNA-mediated targeting of the DNA, which is relatively efficient. The interference of RNA in this technique allows efficient genetic engineering at different loci simultaneously, thereby enabling CRISPR-Cas9 to be an efficient, simple, and user-friendly genome engineering system. This is a significant departure from other genetic engineering approaches using zinc-finger nuclei or effector nuclei, which are time-consuming, costly, and more suitable for large scale studies. However, this does not mean that the new scientific tool is free from challenges.

In the last few years, there have been many genetic editing experiments using the CRISPR-Cas9 tool that have led to concerns regarding this technology's ethical and safe use. In 2017, an American biologist, namely Shoukhrat Mitalipov, experimented using CRISPR-Cas9 on embryos. The biologist attempted to repair a genetic mutation that could lead to fatal heart conditions and aimed for a result wherein the faulty gene isn’t followed the family free. In 2018, Prof. He Jiankui, who worked at the Department of Biology at the Southern University of Science and Technology in Shenzhen, China, conducted a human-gene editing experiment and claimed to create the first of its kind “designer-babies” in the world using CRISPR-Cas9 technology. In his trial, he experimented on embryos he made in an IVF clinic and targeted a gene named “CCR5” and made certain mutations to make the experimental subject resistant to human immunodeficiency virus (hereinafter “HIV). In the same year, researchers in China used the CRISPR-Cas9 technology differently. In an attempt to fix an inherited connective tissue disorder known as Marfan Syndrome, instead of capturing snippets of the invading DNA virus, the researchers swapped the DNA letters. The experiment was done on eighteen embryos, two of which presented certain unintended changes. However, all the embryos were destroyed after the experiment.

All these experiments led to a global controversy and raised serious questions concerning this technology's safe and ethical use. The experiments highlighted the possible use of germline gene-editing technology for non-therapeutic purposes, abuse of genetic editing, and unwarranted genetic enhancements by participants. A significant concern regarding the use of this technology is the possibility of off-target cutting using the Cas-9, which was also seen in the results of two embryos in the Marfan Syndrome experiment. It is paramount to know that any off-target mutation in a participant is tough to detect and can easily result in a permanent alteration of the participant's genetic sequence, which can further cause genome instability or disruption of the participant’s normal gene function. Since the genetic code is passed on to future generations, any off-target mutation or any error in the experiment can lead to potential mutations or incurable diseases if there is a transfer of those genes in other organisms in the future. This is something on which technology may or may not have any control over, and it makes the scientific gene-editing tool extremely unsafe and devastating for the participants and future generations in case of an off-target mutation.

It is significant to understand that the application of CRISPR-Cas9 entails substantial modifications in the heritable DNA of an organism, whether it is a plant, animal, or a human. Hence, it is exceptionally paramount to address the ethical issues concerning the application of CRISPR-Cas9 and talk about the safety, ethical, and security worries regarding the application of the technology to ensure the system's therapeutic delivery. To address these concerns one must look into the legal framework governing the use of this technology.

Governance of Gene-Editing Technology in India

The development and advancement of biotechnology and the CRISPR-Cas9 system are well recognized in India, and there exists a well-drafted, streamlined, divided set of responsibilities for application of the Cas-9. It is well understood that the application of gene-editing technology requires a proper regulatory framework, which is ethical, safe, and secure. Presently, there is no specific law that explicitly prohibits the use of gene-editing technology of germ-line cells. The regulation of this area is facilitated by various guidelines provided by governmental organizations in the country.

The following guidelines regulate the application of genetic modification techniques (including CRISPR-Cas9) in India:

1. The National Guidelines for Gene Therapy Product Development and Clinical Trials, 2019 (hereinafter “Guidelines”) share India’s perspective concerning gene therapy. The Guidelines mention how millions in the nation are victims of complex diseases and inherited monogenic illnesses, of which there is limited or no treatment available. Many of these genetic disorders render a human with a disability for life and make their growth difficult. Hence, the use of gene therapy to conduct and initiate regulatory methods for clinical trials is encouraged. However, the Government of India prohibits the use of gene therapy for academic trials. For this purpose, an academic trial is the clinical trial of a drug approved for a specific claim. Such a trial is initiated by an investigator, research, or academic institution. In such a trial, the aim is to get a new indication or a new administration route, or a new dose or dosage. The result is intended to be used for an academic and research purpose only and not to seek approval of the Central Licensing Authority or any country's regulatory authority for any marketing or commercial purpose. Further, any research and a clinical trial using this technology must ensure that essential tenets of justice, beneficence, autonomy, and non-malfeasance are observed.

As per the Guidelines, all clinical trials using gene therapy products on human participants must safeguard their safety, human rights, dignity, and fundamental freedom. In M. Nagaraj v. Union of India[4] the Hon’ble Supreme Court of India (hereinafter “Supreme Court”) emphasized on Article 21[5] of the Constitution of India and remarked that Right to Life is inclusive of the right to live with human dignity and is the intrinsic value of every being. It held that every human holds human dignity by their existence, and the State cannot deprive a human of their dignity. This value of human dignity is well established in the Guidelines, as it mandates that no clinic trial should violate the same.

2. The Draft Document Regulatory Framework on Genome Edited Organisms: Regulatory Framework and Guidelines for Risk Assessment, 2020 (hereinafter “Regulatory Framework”) lists out essential information that must be gathered in case of gene therapy in humans using Cas-9. It states that all detailed information on gene editing in somatic cells using the technology must be provided with an attachment of documents consisting of prior approvals (for example, consent letter from donor, ethical conformations, etc.) taken from competent authorities like-

o Institutional Biosafety Committee (ISBC),

o Institutional Ethics Committee (IEC),

o Institutional Committee for Stem Cell Research (IC-SCR), and

o Review Committee on Genetic Manipulation (RCGM).

The Regulatory Framework further says that any gene editing in humans must be done in the somatic cells and germline cells. Further, as per the National Guidelines for Stem Cell Research 2017, Indian Council of Medical Research (hereinafter “ICMR”), Department of Health Research (hereinafter “DHR”), and Department of Biotechnology (hereinafter “DBT”), genetic modification can only be done in stem cells, gamete, germline stem cells, or human embryos. The research is restricted to in vitro study purposes, and there is an absolute prohibition on germline editing for human use. Lastly, a justification for conducting research or using genome editing technology and CRISPR-Cas9 is mandatory.

Despite medical guidelines listing out the conduct of gene therapy in India, it is vital to know that these guidelines are not legally binding. In Roche Products India Pvt. Ltd. v. Drugs Controller[6], the Hon'ble High Court of Delhi observed that governmental agencies' guidelines could be enforced in the way of a legally justiciable right. However, this is only in circumstances where the guidelines are created to fill a gap in the existing legal framework. The judgment in Roche Products was in the context of a guideline being used to enforce existing law, and not otherwise. The general rule is that government policies, instructions, and guidelines are administrative and executive guidelines that cannot be enforced by law or courts. Unless the guidelines framed are not backed by legislation, they are not legally binding and judicially enforceable.

However, any non-adherence, deviation or disobedience of these guidelines attracts sanctions. In this sense, if medical practitioners are required to follow code of conduct meant for the registered medical practitioners i.e., the Indian Medical Council (Professional Conduct, Etiquette, and Ethics) Regulations, 2002 (hereinafter “MCI Code”). Any violations of the existing Guidelines given by the ICMR shall amount to professional misconduct. Anyone found guilty of its commission will have their name as a practitioner removed from the register of the Medical Council of India and all State Medical Councils. Hence, any research undertaken requires ethical considerations to be kept in mind; otherwise a medical practitioner may lose their license and shall not practice medicine in India again.

By now, it is well understood that the governance of gene-editing technology in India is through a set of guidelines, which do not have legal validity or binding. The adherence to these guidelines is at the discretion of the physician, researcher, or scientist, and with no direct penalty. The non-compliance to the guidelines concerning gene-therapy is deemed to be unethical and breaches professional conduct. The most a medical practitioner has at stake is their license to practice medicine in India, which is not adequate in any form, especially when the technology in question if abused, can easily compromise a participant’s health, and cause result in more damage than help.

Conclusion

Rising biotechnological and scientific advancements highlight the excellent potential in germline-editing and applying gene-editing technologies to change human life positively. The CRISPR-Cas9 system is proof of how far scientific progression with multiple advantages. However, this technological field is a sensitive playground and has a lot of risks involved. One must understand that the governance of gene therapy in India is through governmental agencies’ guidelines which are not backed by legislation. In a hypothetical scenario, suppose there is any unethical practice of gene therapy in India, and an attempt to create designer babies or conduct a particular gene-editing experiment utilizing the CRISPR-Cas9 technology resulted in off-site targeted mutation. There is no legal liability on the scientist, researcher, or medical practitioner and only the barring of a license in such a scenario. Similarly, the creation of designer babies in India through any research is explicitly prohibited in India through non-mandatory guidelines and is not illegal. However, this does not provide a proper solution to the ethical and safety concerns revolving around CRISPR-Cas9, especially when any act of such “professional misconduct” due to unethical and unsafe use gene-editing technology can severely harm the health of the participant and the future generation.

Presently, India’s present framework concerning gene-editing doesn’t match the kind of governance required to facilitate scientific findings' successful and ethical outcomes. The inadequacy of the current framework of guidelines strongly suggests the need for a legal instrument i.e., legislation that looks into the regulation and application of gene therapy in India and imposes criminal liability on its violators. Technology and science shouldn’t be given the power to regulate humans. Still, if science has the power to present a brighter and healthier future for humans, then one must approach with caution to ensure positive outcomes- and this is why India needs a law on gene editing.

[1] Deborah Ku, The Patentability of the CRISPR-Cas9 Genome Editing Tool, 16 Chi-Kent J. Intell Prop Chicago 408, 409, (2016). [2] Neil Davey, Sonya Davey, Ameya Sampath, Sabrina Shah, Lucia Tamayo, Divya Vatsa, Rajet Vatsa, Raj Dave, The Crispr Controversy: Implications for Science, Law, And Policy in the US and EU, 6 GNLU L. Rev. 13, 18, (2019). [3] James Kozubek, Crispr-Cas9 is Impossible to Stop, 18 Geo. J. Int'l Aff. 112, 113, (2017). [4] (2006) 8 SCC 212 [5] Article 21 of Constitution of India states- “Protection of Life and Personal Liberty- No individual should be deprived of his life or personal liberty except according to procedure established by law.[6] 2016 (66) PTC349 (Del).

Title image source: GenEng News


This article has been written by Priya Ganotra. Priya is a fourth year law student at National Law University, Nagpur.